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8y6k

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Cryo-EM structure of full-length MICAL1 in the autoinhibited state

Structural highlights

8y6k is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.94Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MICA1_HUMAN Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin. Acts by modifying actin subunits through the addition of oxygen to form methionine-sulfoxide, leading to promote actin filament severing and prevent repolymerization (Probable). Acts as a cytoskeletal regulator that connects NEDD9 to intermediate filaments. Also acts as a negative regulator of apoptosis via its interaction with STK38 and STK38L; acts by antagonizing STK38 and STK38L activation by MST1/STK4.^[1] ^[2]

Publication Abstract from PubMed

MICAL proteins represent a unique family of actin regulators crucial for synapse development, membrane trafficking, and cytokinesis. Unlike classical actin regulators, MICALs catalyze the oxidation of specific residues within actin filaments to induce robust filament disassembly. The potent activity of MICALs requires tight control to prevent extensive damage to actin cytoskeleton. However, the molecular mechanism governing MICALs' activity regulation remains elusive. Here, we report the cryo-EM structure of MICAL1 in the autoinhibited state, unveiling a head-to-tail interaction that allosterically blocks enzymatic activity. The structure also reveals the assembly of C-terminal domains via a tripartite interdomain interaction, stabilizing the inhibitory conformation of the RBD. Our structural, biochemical, and cellular analyses elucidate a multi-step mechanism to relieve MICAL1 autoinhibition in response to the dual-binding of two Rab effectors, revealing its intricate activity regulation mechanisms. Furthermore, our mutagenesis study of MICAL3 suggests the conserved autoinhibition and relief mechanisms among MICALs.

Autoinhibition and relief mechanisms for MICAL monooxygenases in F-actin disassembly.,Lin L, Dong J, Xu S, Xiao J, Yu C, Niu F, Wei Z Nat Commun. 2024 Aug 9;15(1):6824. doi: 10.1038/s41467-024-50940-7. PMID:39122694^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schmidt EF, Shim SO, Strittmatter SM. Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein. J Neurosci. 2008 Feb 27;28(9):2287-97. doi: 10.1523/JNEUROSCI.5646-07.2008. PMID:18305261 doi:http://dx.doi.org/10.1523/JNEUROSCI.5646-07.2008
↑ Zucchini D, Caprini G, Pasterkamp RJ, Tedeschi G, Vanoni MA. Kinetic and spectroscopic characterization of the putative monooxygenase domain of human MICAL-1. Arch Biochem Biophys. 2011 Nov;515(1-2):1-13. doi: 10.1016/j.abb.2011.08.004., Epub 2011 Aug 16. PMID:21864500 doi:http://dx.doi.org/10.1016/j.abb.2011.08.004
↑ Lin L, Dong J, Xu S, Xiao J, Yu C, Niu F, Wei Z. Autoinhibition and relief mechanisms for MICAL monooxygenases in F-actin disassembly. Nat Commun. 2024 Aug 9;15(1):6824. PMID:39122694 doi:10.1038/s41467-024-50940-7